Background: PTEN is a tumor suppressor that controls many pathophysiological pathways, including cell proliferation, differentiation, apoptosis and invasiveness. Although PTEN down-modulation is a critical event in neoplastic progression, it becomes apparent that transient and local inhibition of PTEN activity might be beneficial for the healing process.Methods: In the present study, we investigated the impact of PTEN invalidation in mouse intestinal epithelium under a physiological condition and after dextran sulfate sodium (DSS) treatment to induce experimental colitis. PTEN conditional knockout was induced in intestinal epithelial cells after crossing villin-Cre and PTENflox/floxmice.Results: PTEN invalidation alleviates experimental colitis induced by DSS, as evidenced by decreased weight loss during the acute phase, the lower expression of inflammation markers, including the proinflammatory cytokines IFN-γ, CXCL1 and CXCL2, reduced mucosal lesions, and faster recovery after resolution of inflammation. This protective effect might result in part from the sustained proliferation of colonic epithelium, leading to hyperplasia and increased colonic crypt depth under physiological conditions, which was further exacerbated in the vicinity of mucosal injury induced by DSS treatment. Furthermore, PTEN knockout decreased paracellular permeability, thereby enhancing the intestinal barrier function. This process was associated with the reinforcement of claudin-3 immunostaining, especially on the surface epithelium of villin-Cre PTENflox/floxmice.Conclusions: PTEN inactivation exerts a protective effect on the onset of colitis, and the transient and local down-modulation of PTEN might constitute an approach to drive recovery following acute intestinal inflammation.
背景：PTEN是一种肿瘤抑制因子，调控包括细胞增殖、分化、凋亡和侵袭性在内的多种病理生理通路。尽管PTEN下调是肿瘤进展的关键事件，但短暂且局部的PTEN活性抑制可能对愈合过程有益。 方法：本研究探讨了在生理条件下及葡聚糖硫酸钠（DSS）诱导实验性结肠炎后，小鼠肠上皮中PTEN失活的影响。通过杂交villin-Cre与PTENflox/flox小鼠，在肠上皮细胞中诱导了PTEN条件性敲除。 结果：PTEN失活减轻了DSS诱导的实验性结肠炎，表现为急性期体重下降减少、炎症标志物（包括促炎细胞因子IFN-γ、CXCL1和CXCL2）表达降低、黏膜病变减轻以及炎症消退后恢复加快。这种保护作用可能部分源于结肠上皮的持续增殖，导致生理条件下出现增生和结肠隐窝深度增加，在DSS处理诱导的黏膜损伤附近这一现象进一步加剧。此外，PTEN敲除降低了细胞旁通透性，从而增强了肠道屏障功能。这一过程与claudin-3免疫染色的增强相关，尤其在villin-Cre PTENflox/flox小鼠的表面上皮中更为明显。 结论：PTEN失活对结肠炎的发生具有保护作用，短暂且局部的PTEN下调可能成为驱动急性肠道炎症后恢复的一种策略。
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